Abstract
BackgroundAnthracycline-induced liver injury (AILI) is one of the serious complications of anthracycline-based adjuvant chemotherapy for postoperative breast cancer patients. Exosomal miRNAs, as signaling molecules in intercellular communication, play the essential roles in drug-induced liver injury (DILI). However, the expression profiles of them in patients with AILI remains unknown.MethodsSeven post-chemotherapy patients were recruited in this study. After isolated plasma-derived exosomes, small RNA sequencing revealed exosomal miRNA profiles and differentially expressed miRNAs (DE-miRNAs) were identified between the liver injury group and non-liver injury group. miRTarBase and miRDB were used to predict the potential target genes of DE-miRNAs. DILI-related genes were downloaded from the CTD Database. The intersection of predicted genes and DILI-related genes were identified as the AILI-related target genes of the DE-miRNAs. GO annotation and KEGG pathway enrichment analysis were performed by the DAVID database. Furthermore, the protein-protein interaction (PPI) network was established by the STRING database and essential exosomal miRNAs were identified via Cytoscape software.ResultsA total of 30 DE-miRNAs and 79 AILI-related target genes were identified. AILI-related target genes of the DE-miRNAs are significantly enriched in NOD-like receptor signaling pathway, the HIF-1 signaling pathway, and the FoxO signaling pathway. Then, the hub genes were screened and we discovered that IL-6 and SOD2 are the most critical genes that may be involved in the development of AILI through the activation of immune response and the occurrence of oxidative stress, respectively. In addition, we found that miR-1-3p could potentially regulate most of the hub genes in the miRNA-hub gene network.ConclusionWe explored the potential functions of DE-miRNAs and suggested exosomal miR-1-3p might be the essential exosomal miRNA in the pathogenesis of AILI. Moreover, our study provided an experimental basis for experimental verification to reveal the actual function and mechanism of miRNAs in AILI.
Highlights
The liver is the largest internal organ responsible for the selective uptake, metabolism, and excretion of endogenous and exogenous compounds, including drugs
Seven postoperative breast cancer patients who underwent chemotherapy were recruited in our study
The morphology of exosomes was visualized under a transmission electron microscope (TEM), and we found homogeneous cup-shaped vesicles with lipid bilayer membranes (Fig. 2A)
Summary
The liver is the largest internal organ responsible for the selective uptake, metabolism, and excretion of endogenous and exogenous compounds, including drugs. Anthracycline, mainly including doxorubicin and epirubicin, is a class of antibiotics derived from the Streptomyces bacteria and has pleiotropic effects including free radical formation, topoisomerase II inhibition and altered mitochondrial function It is associated with potential long-term effects such as chronic cardiotoxicity and liver injury (Wu et al, 2016; Joerger, 2016). The magnitude of anthracycline-induced liver injury (AILI) in breast cancer patients is rising as a result of the increasing number of longterm cancer survivors and because of the tendency to use higher doses of anthracyclines, as well as combined endocrine treatments with synergistic liver toxic effects. Anthracycline-induced liver injury (AILI) is one of the serious complications of anthracycline-based adjuvant chemotherapy for postoperative breast cancer patients. Exosomal miRNAs, as signaling molecules in intercellular communication, play the essential roles in drug-induced liver injury (DILI).
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